Endothelium-derived relaxing factor (EDRF) is a labile humoral agent which is part of a cascade of interacting agents involved in the relaxation of vascular smooth muscle. EDRF is thus important in the control of vascular resistance to blood flow and in the control of blood pressure. Some vasodilators act by causing EDRF to be released from endothelial cells. (See Furchgott, Ann, Rev. Pharmacol. Toxicol. 24, 175-197, 1984). Recently, Palmer et al. have shown that EDRF is identical to the simple molecule, nitric oxide (NO) (Nature 317, 524-526, 1987). It has been hypothesized for years that many nitrovasodilators that mimic the effect of EDRF, like glyceryl trinitrate, amyl nitrite, NANO.sub.2, and sodium nitroprusside (SNP), do so by virtue of their conversion to a common moiety, namely NO, which is also a vasodilator. (See Kruszyna et al., Tox. & Appl. Pharmacol. 91, 429-438, 1987; Ignarro, FASEB J. 3, 31-36, 1989; Ignarro et al., J. Pharmacol. Exper. Therapeutics 218 (3), 739-749, 1981).
Keefer et al. in U.S. Pat. Nos. 4,954,526, 5,039,705 and 5,155,137 describe primary amine, secondary amine and polyamine NO complexes, their methods of preparation and a method of treating cardiovascular disorders in mammals by administering such complexes to mammals in need thereof. These patents are expressly incorporated herein by reference.
Keefer et al. have recently reported that the above NO complexes may be particularly of use in prophylactically and/or therapeutically treating restenosis in a copending U.S. patent application.
Restenosis is characterized by three mechanistically distinct events: (1) in certain patients, an elastic recoil phenomenon which leads to abrupt closure of vessels within minutes to hours after the balloon angioplasty, (2) early (within two days of balloon injury) platelet aggregation and thrombus formation and (3) late (about two weeks after balloon injury) smooth muscle cell proliferation.
The elastic recoil phenomenon represents the relaxation of the over-stretched vessel segment. Recent observations [Johnson et al., J. Am. Coll. Cardio. 17:419-425, 1990] derived from microscopic examination of atherectomy specimens suggest that this mechanism may occur in up to 25% of angioplasty procedures classified as successful based on the initial angiogram. One possible explanation for this is that endothelial cells are destroyed in the angioplasty procedures; this endothelial cell dysfunction may result in vasospasm. Endotheliumderived relaxing factor (EDRF) has been shown to mediate the control of vascular tone and, thus, may be involved in this vasospasm. Since EDRF has been shown to be identical to nitric oxide [Palmer et al., Nature 317:524-526, 1987], it is reasonable to expect that nitric oxide may replace the EDRF functionality lost when the endothelial cells are destroyed during balloon angioplasty and, thus, prevent the acute closure of vessels.
Within minutes after vessel injury, platelet aggregates and fibrin with entrapped red blood cells are formed [Harker, Am. J. Cardiol. 60:21B-28B, 1987]. These thrombi contain attractants and mitogens for smooth muscle cells. Platelets adhering to the subendothelial surface are largely responsible for the mitogenic activity occurring during this phase of restenosis [Baumgartner and Muggil, in Gordon (ed): Platelets in Biology and Pathology, pp. 23-60, 1976]. Experimental data in animal models mentioned below clearly show the effectiveness of nitric oxide in preventing the aggregation and adhesion of platelets both in vitro and in vivo. It is, thus, reasonable to expect that these same activities will occur when nitric oxide is delivered to the site of vessel injury in mammals.
Smooth muscle cells, probably in response to release of mitogens from injured platelets described above, enter the growth cycle between two and three days after balloon injury and the vast majority of proliferation is completed within seven days [Clowes and Schwartz, Circ. Res. 56: 139-145, 1986]. It is probable that the proliferation of these smooth muscle cells leads to the restenosis observed in one-third to one-half of patients undergoing initial balloon angioplasty. Experimental data described below from in vitro model systems using rat- and human-aorta-derived smooth muscle cells clearly indicates that nitric oxide at concentrations approximating 20-100 .mu.M inhibit by 50% the rate of smooth muscle cell proliferation. Thus, nitric oxide delivered to the site of vessel injury at higher concentrations, e.g., in the range of 200-500 .mu.M, for periods up to about seven days can reasonably be expected to be of prophylactic and/or therapeutic value in restenosis and related conditions.
Although many approaches to ameliorating restenosis have been tried in the past, these approaches have focused on only one primary intervention in the complex cascade of events resulting in restenosis. The use of the polymeric forms of nitric oxide described by Keefer et al. provides not only a multivalent approach to treating the restenosis itself, but also provides the controlled delivery of the nitric oxide in amounts and at times appropriate to maximize the effectiveness of the delivered nitric oxide.